1. Field of the Invention
The invention generally relates to apparatus and therapeutic compositions useful to relieve breathing disorders of the upper airways. This invention more particularly relates to a class of chemicals that activate cold receptors on the mucous membranes of the nose and throat, articles and compositions including these chemicals, and therapeutic uses of these chemicals for relief of nasal and throat discomfort due to inflammation and pain. The particularly preferred embodiment compositions are formulated so as to be delivered as droplets or powder, and comprise “icilin”, a 1,2,3,6-tetrahydropyrimidine-2-one compound.
2. Description of Related Art
Background on icilin compounds. 1,2,3,6-Tetrahydropyrimidine-2-one compounds were described in U.S. Pat. No. 3,821,221(inventors C. Podesva and J. M. Do Nascimento et al., Jun. 28, 1974). These compounds were thought to have depressant and/or stimulant effects on the central nervous system. In 1972, an abstract described a compound in this series called AG-3-5 (1[2-hydroxyphenyl]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyrimidine-2-one). This prototype elicited a syndrome of “wet dog shake behavior” in rats and monkeys accompanied by hyperthermia, hyperactivity and ptosis. Wei (Chemical stimulants of shaking behavior. Journal of Pharmacy and Pharmacology 28: 722-724, 1976) provided the first detailed report of the actions of AG-3-5 in animals and noted that shaking behavior similar to those of a dog when wet could be evoked in various laboratory animals such as the rat, mouse, cat, dog, gerbils, guinea pigs and hamsters.
Subsequently, Wei (Pharmacological aspects of shaking behavior produced by AG-3-5, TRH, and morphine withdrawal. Federation Proceedings 40: 1491-1496, 1981) reported that 0.1 mg of AG-3-5, dissolved in propylene glycol, applied to the dorsum of the tongue elicited prickling sensations of cold and ingestion of 6 mg mixed in orange juice, on one occasion out of three, produced sensations of coolness on the cheeks and on the inner surfaces of the arms and legs. It was hypothesized that AG-3-5 may produce specific activation of receptors for cold, and that stimulation of these receptors accounted for the shaking seen in laboratory animals. In a subsequent publication (E. T. Wei and D. A. Seid. AG-3-5: A chemical producing sensations of cold. Journal of Pharmacy and Pharmacology 35: 110-112, 1983) the effects of AG-3-5 on shaking behavior in the rat were compared to those of menthol and AG-3-5 was shown to be 400 times more potent than menthol on a molar basis on this behavioral endpoint. AG-3-5 was less toxic than menthol, as measured by the oral median lethal dose in rats.
AG-3-5 was named icilin by Wei because of its cold-producing properties. Icilin has recently become commercially available from Tocris Cookson Inc., Ellisville, Mo. 63021 and Phoenix Pharmaceuticals, Belmont, Calif., USA.
Recently, two independent groups simultaneously cloned a biological macromolecule (called a receptor) from trigeminal sensory neurons of the rat. These receptors belong to the transient receptor potential (TRP) family of ion channels and respond to cold temperature and to menthol. Using a sample provided by Wei, McKemy et al. (Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416: 52-58, 2002) showed that icilin was about 200 times more potent than menthol in eliciting ion channel current changes in the cloned and transfected TRP(M8) receptor. The ion permeability changes elicited in transfected cells were more robust with icilin than those elicited by menthol, and the presence of extracellular calcium was required for activity. Menthol currents did not require extracellular calcium.
The chemical structure of icilin bears little similarity to that of menthol; the former chemical being a pyrimidine-2-one attached to two phenyl rings, and the latter a cyclohexanol derivative. Activation of the TRP(M8) receptor on the neuronal membrane may lead to depolarization of the sensory nerve ending and send action potentials towards the spinal cord and brain that are eventually recognized as psychic signals of skin stimulation. The term “agonist” is used by pharmacologists to denote a chemical substance that activates biological events. Hence, icilin and its analogs may be classified as “cold receptor agonists.”
Background on treatment of nasal and upper airway irritation, stuffiness, and congestion. The nose is the entrance to the respiratory tract. It serves as a conduit for inspired and expired air. When one or both sides of the nose are obstructed, this impairs nasal functioning and is perceived as an uncomfortable condition. All the nasal cavity bony surfaces, including the paranasal sinuses, are lined by tissue called mucosa. This mucosa contains blood vessels, nerves, and small glands that secrete mucus and fluids into the nasal cavity. The nose is also richly supplied by sensory nerves that detect pain, temperature, pressure and odor, and by motor nerves that regulate secretions and blood flow. The nasal mucosa humidifies and warms the inspired air, hence it receives a large blood flow and the cells maintain a high degree of metabolic activity. Inflammation of the nasal mucosa caused by allergy, infections, or irritants and the like, will cause the mucosa to secrete fluids, swell, and obstruct. When the nasal membranes increase in volume, the area available through which air can pass is diminished, and therefore one experiences a sense of “stuffiness”, resistance to inspiration, or a feeling of nasal obstruction. The nose can also become “runny” (rhinorrhea) and fluid accumulation and discharge add to the feeling of congestion. If either or both sides of the nose are obstructed, the asymmetry in airflow is perceived as an unpleasant condition.
The following descriptions give an over-view of some quantitative dimensions of nasal function. The normal air intake is about 10,000 liters per day and nasal secretions contribute about 30 ml of fluids to humidify each 1000 liters. The relative humidity of air inhaled via the nose is about 60% when it goes past the nose, but it is only about 5% when the air is breathed through the mouth. The relative humidity of air in the bronchi is 100% at body temperature and this humidification, contributed by blood flow through the mucosa, is required to maintain ciliary activity and prevent epithelial changes in the bronchial mucosa. Desiccation of the bronchial surface for more than 2 to 3 hours can cause mucosal changes that result in thickening of secretions, irritation, and increased susceptibility to infection.
Airflow into and out of the lungs is a function of:                AIRFLOW˜FORCE/RESISTANCE        RESISTANCE˜1/RADIUS4         AIRFLOW˜FORCE×RADIUS4         
Force for inspiration is the work done by the respiratory muscles to create negative intra-thoracic pressure and resistance is determined by the diameter of the airway and the viscosity of its contents. According to the Poiseuille equation, a small decrease in the radius of the airway is magnified to the fourth power and expressed as increased resistance to airflow. The nasal passages contribute 50% of the total resistance to overall airflow. Hence, any nasal congestion or obstruction will require greater effort to bring air to gas exchange surface in the lower respiratory tract.
Nasal stuffiness and congestion has many causes, the most common being “rhinitis”, a technical term meaning the condition of inflammation of the membranes lining the nose. Rhinitis is characterized by nasal congestion, rhinorrhea (“runny nose”), sneezing, itching of the nose and/or postnasal drainage. A common form of rhinitis is seasonal allergic rhinitis which is caused by an immunoglobulin E (IgE)-mediated reaction to seasonal aeroallergens. Typical seasonal aeroallergens are pollens and molds. The length of seasonal exposure to these allergens is dependent on geographic location. Perennial allergic rhinitis is caused by an IgE-mediated reaction to perennial environmental aeroallergens. These may include dust mites, molds, animal allergens, or certain occupational allergens, as well as pollen in areas where pollen is prevalent perennially. Allergic rhinitis frequently coexists with allergic conjunctivitis (of the eye) and is often present in individuals with asthma. Rhinitis can also be caused by food allergies. Some individuals, without evidence of allergic sensitization, will have rhinitis in reaction to nonspecific irritant stimuli such as cold dry air, perfumes, paint fumes, and cigarette smoke. This condition is called vasomotor rhinitis. Severe rhinitis may result from injury to the nasal membranes such as occurs after smoke inhalation, sinusitis, or after nasal surgery.
The rhinitis that is most familiar to everyone is infectious rhinitis caused by viruses such as the common cold virus. Initially, viral rhinitis is characterized by clear, watery rhinorrhea that is accompanied by sneezing and nasal obstruction. Edema of the nasal mucosa produces occlusion of the sinus ostia, with resulting facial pain, or of the Eustachian tube, with resulting ear fullness. The nasal drainage may become cloudy due to the presence of micro-organisms and cellular debris. Responsible viruses include rhinoviruses, respiratory syncytial virus, parainfluenza, influenza and adenoviruses. Fever may accompany viral rhinitis, especially if there is bacterial superinfection by streptococcal organisms.
Rhinosinusitis, in which inflammation of the mucosa of the nasal sinuses occur together with the nasal membranes, is especially aggravating because it is accompanied by prolonged mucopurulent nasal discharge, facial pain and pressure, olfactory disturbance, and post-nasal drainage with cough. Conditions of the upper airways in which rhinitis is a component are described in detail by M. S. Dykewicz et al. (Diagnosis and management of rhinitis: Complete guidelines of the Joint Task Force on practice parameters in allergy, asthma and immunology. Annals Allergy Asthma Immunology 81: 478-518, 1998).
The time-course of the nasal response to irritants can be exactly chronicled in the laboratory. In patients with sensitivity, provocation with the allergen will result in an immediate response of severe sneezing, itching, hyper-secretion and a moderate sense of obstruction. These events peak at 30 minutes and last for about 90 minutes after provocation. The immediate response is followed by the late and/or delayed response in which severe nasal congestion and a sense of obstruction is the primary symptom. The late response to a single challenge begins 4 hours after provocation, peaks at 8 hours, and fades at 12 hours. The delayed response begins at 24 hours after provocation, peaks at 36 hours and fades at 56 hours. During the peak time of late nasal obstruction, the nostril to nasopharynx pressure gradient rises by 20 to 24 cm of water as measured by rhinomanometry, illustrating the increase in airflow resistance caused by rhinitis.
Nasal stuffiness is an important contributory factor to other breathing disorders of the upper airways, such as snoring and sleep apnea, as reviewed by M. B. Scharf and A. P. Cohen (Diagnostic and treatment implications of nasal obstruction in snoring and obstructive sleep apnea. Annals Allergy Asthma Immunology 81: 279-290, 1998). As mentioned previously, airflow through the nasal passages contributes to 50% of respiratory resistance. When airflow is impeded, there must be compensatory increased respiratory force and mouth breathing commences. While individuals with nasal congestion may be capable of breathing through the nose while awake, they must exert more effort to draw air through the nasal airway during sleep because pharyngeal muscles relax during sleep and this relaxation narrows the airway passage in the back of the mouth. The additional respiratory effort produces a greater vacuum in the throat, which pushes the throat tissues, including the tongue, towards the pharynx and further reduces the space for airflow. Mouth breathing also reduces pharyngeal airspace and contributes to snoring and the related condition known as obstructive sleep disorder.
Snoring and obstructive sleep disorders (also called obstructive sleep hypoapnea/apnea) are breathing disorders of the upper airways. The pathophysiological bases of these disorders are described in many monographs and an excellent review by Scharf and Cohen (supra) is available for reference. Briefly, snoring consists of audible sounds produced during sleep caused by vibrations of throat muscles. The throat muscles vibrate more readily when they are relaxed during sleep and when air velocity is high. Obstruction of the pharynx by hypertrophied adenoids (tonsils) or obesity can also cause excessive snoring. J. M. Truelson in an eMedicine article provides an elegant description of the underlying mechanisms:
“Two basic principles of fluid flow can be applied to give some additional insight to the effects of airway narrowing—the Bernoulli principle and the Venturi effect.
The Bernoulli principle describes fluid flow in a column. A partial vacuum exists at the outer edges of a column of moving fluid such that the faster the flow, the greater will be the partial vacuum. The smaller the column, the faster the flow. An every day example of this is a paper straw. If you suck too hard on a straw, it collapses. If you suck less hard or the straw is more rigid, it does not collapse.
The Venturi effect deals with airflow accelerating as a current of air enters a narrow passageway. The wind blowing between buildings or water coming out of a hose partially occluded by the thumb are examples of this effect. Added to these effects are the distensible and moveable walls of the column of air in question—the pharynx.
Sleep apneics and normal individuals differ in their closing pressures and airway resistance due to the anatomy and the pliability of the walls of the pharynx. In a non-snoring adult the negative pressure required to close the upper airway is less than (more negative) −25 cm water. Snoring adults have a much more pliable airway, with closure during sleep occurring at pressures ranging from −2 to −10 cm water.
The cumulative effect of all these factors results in a vicious cycle, which eventuates in maximal airway closure permitted by the distensibility and relaxation of the airway. The cycle is only broken by arousal, disrupting the sleep.”
Individuals with persistent snoring are not considered “normal” because snoring indicates some degree of airway obstruction. If snoring and sleep disturbances do not self-correct, the sleep disruption will cause fatigue, daytime sleepiness, short-term memory loss, decreased job effectiveness, and increased risk of motor vehicle accidents. The individual is less alert. There is also evidence of increased risk of heart attacks, strokes, high blood pressure, mood alteration, and sexual dysfunction in such individuals.
Ultimately, when airflow cannot be maintained by inspiratory force for any reason, the individual will progress to respiratory failure and the technical term describing the difficulty in breathing is “dyspnea.” Dyspnea as a symptom is expressed as sensations of choking and suffocation. As a sign, it is expressed as labored breathing and inadequate ventilation with a rise in plasma carbon dioxide tension. Dyspnea occurs in serious disorders such as pneumonia, congestive heart failure, asthma, chronic obstructive pulmonary disease, emphysema, cystic fibrosis, muscular paralysis or dystrophy, Parkinson's disease, lung cancer, debilitation from wasting diseases and the like. The sense of suffocation, encompassed in dyspnea, is a frightening experience at the end of life.
Menthol, camphor and eucalyptus oil have been used since ancient times as remedies for nasal irritation and for refreshment of nasal sensations. These compounds are, however, not effective for rhinitis and may in fact exacerbate nasal congestion and obstruction, especially in the late and delayed stages of rhinitis. Sympathomimetic vasoconstrictors (decongestants) reduce nasal blood flow, but have a number of adverse side-effects, including rebound hyperemia (rhinitis medicamentosum). Disodium cromoglycate is effective for allergic rhinitis, but onset of effect is slow. By far, the most effective medications for seasonal, perennial and non-allergic rhinitis are the potent glucocorticosteroids administered as nasal sprays in manual pump-operated metered atomizers (e.g. Flonase®, Rhinocort®, Nasonex® and Nasocort®), as mouth or nasal inhalers or as nose-drops. These drugs reduce nasal membrane inflammation and the symptoms and signs of allergic rhinitis. These compounds do not, however, provide immediate sensory relief for nasal stuffiness, and are of limited efficacy for relieving the discomforts of infectious rhinitis and rhinosinusitis. Corticosteroids are effective in rhinitis associated with eosinophil-dominated inflammation (e.g. allergic rhinitis), but not in rhinitis associated with neutrophil-dominated inflammation (e.g. common cold, infectious rhinitis, sinusitis).
Spray mists and nose drops containing mixtures of herbal oils, including peppermint oil, are available as non-FDA regulated products for snoring, but no clinical evidence of efficacy for these preparations has been published in the medical literature. Mechanical devices for continuous positive airway pressure (CPAP) assisted breathing are available for severe snoring, obstructive sleep disorders, and for dyspnea from respiratory disorders. These devices are expensive and require patient cooperation.